The epidemics of obesity and type-2 diabetes mellitus (T2DM) that have developed in the past 50 years are almost certainly environmental, and can be reconciled with acquired hypothalamic dysregulation of food intake. Insulin insensitive T2DM patients are typically overweight or obese and often have difficulty maintaining recommended diets. This patient population has chronically elevated insulin levels which are known to negatively influence regulation of the orexigenic hormone ghrelin and cause progressive dysfunction in meal-insulin-ghrelin dynamics. Thus, as obese patients become progressively less insulin sensitive, their ability to suppress hunger after meals declines leading in theory to more frequent cravings and hunger. The Central Thesis behind our study is that the typical western diet is high in protein and saturated fat, derived mainly from animal sources, and is a significant contributor to the impaired insulin sensitivity found in obese T2DM patients. The overall hypothesis of this application is that by utilizing a plant-based diet (devoid of animal products thus low in saturated fat and protein) in obese T2DM subjects, insulin sensitivity will improve and restore ghrelin dynamics towards that of lean insulin-sensitive individuals. A six-week, prospective, randomized nutritional intervention will be conducted in obese T2DM subjects who receive all meals prepared for them that are calorically matched to maintain stating weight, and consist of a typical 'western'diet (based on NHANES 2000) for the first two weeks followed by randomization to continue or switch to a 'plant-based'diet for four weeks. Fasting insulin and glucose measurements throughout will detect changes in insulin sensitivity (QUICKI method), while extended oral glucose testing will detect changes in pre and post-prandial ghrelin dynamics. The specific aims of this study are 1) to demonstrate that a plant-based diet (devoid of animal products) will significantly improve insulin sensitivity in T2DM subjects, as compared with subjects ingesting a typical 'western'diet whose protein and fat are derived mainly from animal products. 2) Demonstrate that a plant-based diet will change the temporal pattern of ghrelin release towards that found in insulin sensitive, lean subjects- i.e. enhancing the pre-prandial rise and post- prandial suppression of ghrelin. 3) Determine the time-course for improvement in insulin sensitivity and ghrelin dynamics following the introduction of a plant-based diet. PUBLIC HEALTH RELEVANCE: For 26.8 million U.S. citizens, the individual burden of Type 2 Diabetes Mellitus (T2DM) reduces quality of life and shortens life span, while the financial burden to the U.S. is projected to be $198 billion in 2010.1 The fact that obesity and T2DM are increasing in developing countries which adopt a western diet along with the existing epidemic of T2DM in the U.S., suggests that patterns of nutritional intake should be central to investigations of the mechanisms underlying impaired insulin action and appetite dysregulation. A plant-based diet may hold the key to restoring insulin sensitivity and appetite regulation in T2DM.